OBJECTIVE: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature.
METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed.
RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001).
CONCLUSIONS: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.

Chronic inflammatory conditions, such as juvenile idiopathic arthritis, are associated with growth failure. Growth failure appears to be correlated with both the effects of inflammation and negative effects of glucocorticoids (used as therapeutic option) on the growth hormone axis and locally on the growth plate and bone metabolism. In the last decade, the introduction of biologics has changed the disease course regarding consequences and outcomes. Anyway in some cases, treatment with biologics has failed in restoring normal growth in patients with juvenile idiopathic arthritis; in contrast, several studies have reported improved height velocity and growth rate in patients with juvenile idiopathic arthritis treated with growth hormone. This study aimed to evaluate the impact of growth hormone treatment on the growth and pubertal development in juvenile idiopathic arthritis patients through a narrative review of the literature over the last four decades.

UNASSIGNED: The safety of recombinant human growth hormone (rhGH) treatment in childhood and the role of rhGH therapy in promoting tumorigenesis and progression have been the subject of debate for decades. We aimed to systematically assess the relationship between rhGH therapy in children and adolescents and clinical outcomes, including all-cause mortality, cancer mortality, cancer incidence, and risk of the second neoplasm.
UNASSIGNED: Literature retrieval, study selection, and data extraction were completed independently and in duplicate. Effect-size estimates are expressed as standardized mortality ratios (SMRs), standardized incidence ratio (SIR), and relative risk (RR) with a 95% CI.
UNASSIGNED: Data from 24 articles, involving 254,776 persons, were meta-analyzed. Overall analyses revealed the association of rhGH therapy was not statistically significant with all-cause mortality (SMR = 1.28; 95% CI: 0.58-2.84; P = 0.547; I 2 = 99.2%; Tau2 = 2.154) and cancer mortality (SMR = 2.59; 95% CI: 0.55-12.09; P = 0.228; I 2 = 96.7%; Tau2 = 2.361) and also cancer incidence (SIR = 1.54; 95% CI: 0.68-3.47; P = 0.229; I 2 = 97.5%; Tau2 = 2.287), yet statistical significance was observed for second neoplasm (RR = 1.77; 95% CI: 1.33-2.35; P = 0.001; I 2 = 26.7%; Tau2 = 0.055). Differences in the geographic region, gender, treatment duration, mean rhGH dose, overall rhGH exposure dose, and initial disease accounted for heterogeneity in the subgroup analyses.
UNASSIGNED: Our findings indicate that the rhGH therapy is not related to all-cause mortality and cancer mortality and cancer incidence, yet it seems to trigger a second tumor risk. Future prospective studies are needed to confirm our findings and answer the more challenging question regarding the optimal dose of rhGH therapy in children and adolescents.

OBJECTIVE: Idiopathic short stature (ISS) is a recognized, albeit a controversial indication for treatment with recombinant human growth hormone (rhGH).The objective of the present study was to conduct a systematic review of the literature and meta-analyses of selected studies about the use of rhGH in children with ISS on linear growth and adult height (AH).
METHODS: A systematic literature search was conducted to identify relevant studies published till February 28, 2017 in the following databases: Medline (PubMed), Scopus and Cochrane Central Registry of Controlled Trials. After exclusion of duplicate studies, 3,609 studies were initially identified. Of those, 3,497 studies were excluded during the process of assessing the title and/or the abstract. The remaining 112 studies were evaluated further by assessing the full text; 21 of them fulfilled all the criteria in order to be included in the current meta-analysis.
RESULTS: Children who received rhGH had significantly higher height increment at the end of the first year, an effect that persisted in the second year of treatment and achieved significantly higher AH than the control group. The difference between the two groups was equal to 5.3 cm (95% CI: 3.4-7 cm) for male and 4.7 cm (95% CI: 3.1-6.3 cm) for female patients.
CONCLUSIONS: In children with ISS, treatment with rhGH improves short-term linear growth and increases AH compared with control subjects. However, the final decision should be made on an individual basis, following detailed diagnostic evaluation and careful consideration of both risks and benefits of rhGH administration.

Objective: There are numerous reasons for short stature, including mutations in osteochondral development genes. ACAN, one such osteochondral development gene whose heterozygous mutations can cause short stature, has attracted attention from researchers in recent years. Therefore, we analysed six cases of short stature with heterozygous ACAN mutations and performed a literature review. Methods: Clinical information and blood samples from six probands and their family members were collected after consent forms were signed. Gene mutations in the probands were detected by whole-exome sequencing. Then, we searched the literature, performed statistical analysis and summarized the characteristics of all reported cases. Results: We identified six novel mutations of ACAN: c.1411C>T, c.1817C>A, c.1762C>T, c.2266G>C, c.7469G>A and c.1733-1G>A. In the literature, more than 200 affected individuals have been diagnosed genetically with a similar condition (height=-3.14±1.15 standard deviation score (SDS)). Among affected individuals receiving growth promoting treatment, their heights before and after treatment was -2.92±1.07 SDS vs. -2.14±1.23 SDS (p<0.001). As of July 1st, 2019, fifty-seven heterozygous ACAN mutations causing non-syndromic short stature had been reported, including the six novel mutations found in our study. Approximately half of these mutations can lead to protein truncation. Conclusions: This study used clinical and genetic means to examine the relationship between the ACAN gene and short stature. To some extent, clear diagnosis is difficult, since most of these affected individuals\' characteristics are not prominent. Growth promoting therapies maybe beneficial for increasing their heights.